Burden and severity of children's hospitalizations by respiratory syncytial virus in Portugal, 2015–2018

Abstract Background Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory infection (ALRI) in young children and is of considerable burden on healthcare systems. Our study aimed to evaluate ALRI hospitalizations related to RSV in children in Portugal. Methods We reviewed hospitalizations potentially related to RSV in children aged <5 years from 2015 to 2018, using anonymized administrative data covering all public hospital discharges in mainland Portugal. Three case definitions were considered: (a) RSV‐specific, (b) (a) plus unspecified acute bronchiolitis (RSV‐specific & Bronchiolitis), and (c) (b) plus unspecified ALRI (RSV‐specific & ALRI). Results A total of 9697 RSV‐specific hospitalizations were identified from 2015 to 2018—increasing to 26 062 for RSV‐specific & ALRI hospitalizations—of which 74.7% were during seasons 2015/2016–2017/2018 (November–March). Mean hospitalization rates per season were, for RSV‐specific, RSV‐specific & Bronchiolitis, and RSV‐specific & ALRI, respectively, 5.6, 9.4, and 11.8 per 1000 children aged <5 years and 13.4, 22.5, and 25.9 in children aged <2 years. Most RSV‐specific hospitalizations occurred in healthy children (94.9%) and in children aged <2 years (96.3%). Annual direct costs of €2.4 million were estimated for RSV‐specific hospitalizations—rising to €5.1 million for RSV‐specific & ALRI—mostly driven by healthy children (87.6%). Conclusion RSV is accountable for a substantial number of hospitalizations in children, especially during their first year of life. Hospitalizations are mainly driven by healthy children. The variability of the potential RSV burden across case definitions highlights the need for a universal RSV surveillance system to guide prevention strategies.


| INTRODUCTION
Respiratory syncytial virus (RSV) is responsible for seasonal diseases causing a great burden on healthcare systems across the world. 1 RSV is the leading cause of acute lower respiratory infection (ALRI) in children and a major driver of childhood hospitalizations. [2][3][4][5] The clinical manifestations can range from mild to severe respiratory infections, including bronchiolitis and pneumonia. 1 Globally, 33.0 million RSVassociated ALRI episodes were estimated to have occurred in children <5 years in 2019, causing around 3.6 million RSV-associated ALRI hospital admissions, 26,300 RSV-associated ALRI in-hospital deaths, and 101,400 RSV-attributable overall deaths. 5 Nearly 20% of the infections, 39% of the hospitalizations, 51% of the in-hospital mortality, and 45% of the total RSV-attributable overall deaths across the world occurred in infants younger than 6 months. 5 Preterm infants or children with underlying medical conditions are more likely to suffer from serious disease and have higher rates of morbidity and mortality. 1 Furthermore, children with severe RSV infection early in life are at greater risk of developing subsequent wheezing, hyperreactive airway disease, and asthma in later childhood. 1,6,7 Current prevention strategies are focused on specific at-risk children, despite evidence that most hospitalizations for RSV occur in previously healthy children born at term. [8][9][10][11][12] The development of RSV vaccines and immunoprophylactic agents 13 has given a new impetus to research on the pediatric RSV burden across the world, particularly on severe (hospitalized) cases, as more evidence is required to prepare their introduction to health systems. Particularly, a more granular understanding of the true burden in the populations that may benefit the most from preventive measures is required to prevent these frequently severe hospitalizations and short-term healthcare episodic burdens, as well as associated long-term respiratory morbidity. 7,13 In Portugal, there are no recent studies on the burden of RSVrelated hospitalizations, using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10 CM), which has introduced more RSV-specific diagnosis codes. Furthermore, there are no studies assessing RSV-related hospitalizations in children between 2 and 5 years. The most comprehensive study covers acute bronchiolitis in children aged <2 years. 14,15 Recent evidence suggests that combining RSV with other unspecified ALRI diagnoses may help overcome the obstacle of underestimating RSV cases in children aged <5 years, without sacrificing high specificity, particularly in hospitals with lower virus identification resources-as cases are often coded according to clinical manifestations but without specifying the infectious agent causing the disease. 3,16,17 Indeed, Cai et al. 16 showed that RSVspecific ICD-10 codes alone had high specificity (99.8%) and poor sensitivity (6%) but, when combined with general ALRI ICD-10 codes, the specificity remained high (>90%) and the sensitivity increased (44%).
Hamilton et al. have also identified this combination of ICD-10 codes as the top-performing algorithm to identify RSV cases. 18 In our study, we aimed to describe the burden of potentially RSVrelated hospitalizations in Portuguese mainland public hospitals, in children under 5 years of age, from epidemic seasons 2015 to 2018, and analyze the incidence and costs of the hospitalizations for the National Health System (NHS). Secondary objectives included the analysis of RSV seasonality, the description of the clinical and demographic characteristics of hospitalized patients, and the outcomes and severity indicators of the episodes.

| Study design
Anonymized administrative data on hospitalizations potentially due to RSV in children aged <5 years (January 2015-December 2018) were reviewed. The data were provided by the Administração Central do Sistema de Saúde (ACSS), which collects administrative and clinical data for all hospitalization episodes in Portuguese public hospitals, including information on diagnoses and procedures performed during hospital stay, which are coded using the ICD-9 CM and ICD-10 CM/PCS.

| RSV case definition
A child was classified as having an RSV-related event based on hospital discharge ICD-9/10 codes, if coded as a primary or secondary diagnosis, according to three distinct case definitions (Table 1) Unless otherwise stated, results are presented for the RSV-specific definition. Case definitions were based on findings from Cai et al. 16 Total hospitalizations excluded admissions related to routine birth (ICD-9 CM codes V30.x through V39.x or ICD-10 CM Z38 as a primary diagnosis). All episodes with a length of hospital stay (LOS) of less than 24 h are not included in the database.
The unit of analysis (case) was the hospitalization episode. This means that a patient who was admitted to the hospital multiple times was accounted for each time separately. An exception was made for the analysis of mean cost per patient, where the cost of all included cases was divided by the number of unique patients.

| RSV season
To increase accuracy for RSV potential cases, as is described in temperate climates, 2,19 data were analyzed by epidemic season

| Risk factors
The additional ICD-9/10 codes for diagnostic information were used to identify children who had at least a risk factor for severe RSV (Table S1), in any primary or secondary diagnosis field. The following  Mechanical ventilation was used as a surrogate indicator of intensive care unit (ICU) admissions, as these are not separately identified in the database. 14 Additionally, a respiratory severity marker was created, combining the following procedures and diagnosis: supplementary oxygen therapy, hypoxemia, invasive and noninvasive ventilation, respiratory failure, and other abnormalities of breathing (codes detailed in Table S2). Oxygen therapy is recommended in Portugal when blood oxygen saturation and pulse (SpO 2 ) is ≤92%, 21 a level that may be considered a predictor of clinical deterioration. 22

| Costs
Only direct costs were estimated, using a diagnosis-related group

| Ethical considerations
Data were provided anonymized from ACCS and may be used for research purposes without ethics committee approval or informed consent.

| Hospitalization rate
Annual RSV-specific hospitalization rate during the analyzed epidemic The following risk factors were considered to classify children as having a risk factor for RSV: heart disease, neuromuscular disorders, bronchopulmonary dysplasia, Down syndrome, immunodeficiency, congenital disorders of the respiratory system, congenital musculoskeletal anomalies, and cystic fibrosis. Prematurity, low birth weight, and exposure to tobacco were not included.
T A B L E 3 Descriptive statistics on length of stay and costs per patient of respiratory syncytial virus-related hospitalizations in patients aged <5 years, by age group and presence or absence of at least one risk factor, in Portuguese public hospitals between 2015/2016 and 2017/2018 Refers to the costs of all hospitalizations associated with the same patient. In case the same patient had more than one hospitalization with different ages, comorbidities status, or RSV classifications, these were analyzed as two separate patients for the purpose of this analysis. b The following risk factors were considered to classify children as having a risk factor for RSV: heart disease, neuromuscular disorders, bronchopulmonary dysplasia, Down syndrome, immunodeficiency, congenital disorders of the respiratory system, congenital musculoskeletal anomalies, and cystic fibrosis. Prematurity, low birth weight, and exposure to tobacco were not included. Refers to the costs of all hospitalizations associated with the same patient. In case the same patient had more than one hospitalization with different ages, comorbidities status, or RSV classifications, these were analyzed as two separate patients for the purpose of this analysis. b The following risk factors were considered to classify children as having a risk factor for RSV: heart disease, neuromuscular disorders, bronchopulmonary dysplasia, Down syndrome, immunodeficiency, congenital disorders of the respiratory system, congenital musculoskeletal anomalies, and cystic fibrosis. Prematurity, low birth weight, and exposure to tobacco were not included.

| Relevant medical history associated with the child's birth
Prematurity was registered as a diagnosis in 1.2% of the RSV-specific cases (reaching a maximum of 3.4% in the age group of 0-1 month), low birth weight in 0.7% of the cases, and exposure to tobacco in 1.5% of the cases.

| Length of stay
Mean (SD) and median (IQR) LOS per episode are presented in Table 3. The median (IQR) LOS for RSV-specific hospitalization was

| Direct healthcare cost
The total direct medical cost of RSV-specific hospitalizations was €7. Mean (SD) and median (IQR) costs per patient are presented in which is closer to our lower bound estimate. However, most studies included only RSV-confirmed cases, an approach which may also underestimate the true burden of RSV, unless systematic testing is performed upon admission. 25 Rates obtained using active laboratoryconfirmed surveillance were found to be almost twice as high as those obtained using RSV-specific ICD-10 hospital discharge codes and more than three times the rate in children aged 2-4 years. 24 In Portugal, a study of 6743 samples analyzed through the influenza surveillance system (2014-2018) in children aged <5 years found that 72.5% were positive for RSV. 20 Bronchiolitis and pneumonia were significantly associated with RSV-positive cases among children aged <5 years, which is consistent with our findings. Also, Hall et al.
observed that bronchiolitis was the most frequent diagnosis in RSVpositive inpatients aged <12 months (reported in 85% of cases), whereas in children aged between 2 and 5 years, pneumonia (51%) and acute asthma (60%) were the most frequent diagnoses. 9 This supports the relevance of broader RSV case definitions, particularly for children aged >2 years.
Importantly, studies converge in the observation of the highest RSV hospitalization rates in the youngest age groups. 10  An annual cost of €2.4 million was estimated for RSV-specific

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.13066.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from IQVIA, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of IQVIA.